α-D-Gal-cyclophellitol cyclosulfamidate is a Michaelis complex analog that stabilizes therapeutic lysosomal α-galactosidase A in Fabry disease

Marta Artola; Christinne Hedberg; Rhianna J. Rowland; Lluís Raich; Kassiani Kytidou; Liang Wu; Amanda Schaafa; Maria Joao Ferraz; Gijsbert A. van der Marel; Jeroen D. C. Codée; Carme Rovira; Johannes M. F. G. Aerts; Gideon J. Davies; Herman S. Overkleeft

doi:10.1039/C9SC03342D

α-D-Gal-cyclophellitol cyclosulfamidate is a Michaelis complex analog that stabilizes therapeutic lysosomal α-galactosidase A in Fabry disease

Marta Artola, Christinne Hedberg, Rhianna J. Rowland, Lluís Raich, Kassiani Kytidou, Liang Wu, Amanda Schaafa, Maria Joao Ferraz, Gijsbert A. van der Marel, Jeroen D. C. Codée, Carme Rovira, Johannes M. F. G. Aerts, Gideon J. Davies, Herman S. Overkleeft

Chemistry

Research output: Contribution to journal › Article › peer-review

Abstract

Fabry disease is an inherited lysosomal storage disorder that is characterized by a deficiency in lysosomal α-D-galactosidase activity. One current therapeutic strategy involves enzyme replacement therapy, in which patients are treated with recombinant enzyme. Co-treatment with enzyme active-site stabilizers is advocated to increase treatment efficacy; a strategy that requires effective and selective enzyme stabilizers. Here, we describe the design and development of an α-D-gal-cyclophellitol cyclosulfamidate as a new class of neutral, conformationally-constrained competitive glycosidase inhibitor that acts by mimicry of the Michaelis complex conformation. We found that D-galactose-configured α-cyclosulfamidate 4 effectively stabilizes recombinant human α-D-galactosidase (agalsidase beta, Fabrazyme®) both in vitro and in cellulo.

Original language	English
Number of pages	13
Journal	Chemical Science
Early online date	20 Aug 2019
DOIs	https://doi.org/10.1039/C9SC03342D
Publication status	E-pub ahead of print - 20 Aug 2019

Bibliographical note

Access to Document

10.1039/C9SC03342DLicence: CC BY-NC

Artola et al. Chem Sci. manuscript
© 2019
Accepted author manuscript, 1.54 MBLicence: CC BY-NC

Cite this

Artola, M., Hedberg, C., Rowland, R. J., Raich, L., Kytidou, K., Wu, L., Schaafa, A., Ferraz, M. J., van der Marel, G. A., Codée, J. D. C., Rovira, C., Aerts, J. M. F. G., Davies, G. J., & Overkleeft, H. S. (2019). α-D-Gal-cyclophellitol cyclosulfamidate is a Michaelis complex analog that stabilizes therapeutic lysosomal α-galactosidase A in Fabry disease. Chemical Science. Advance online publication. https://doi.org/10.1039/C9SC03342D

@article{f6dce285bcee4a52b180d3900c337fd8,

title = "α-D-Gal-cyclophellitol cyclosulfamidate is a Michaelis complex analog that stabilizes therapeutic lysosomal α-galactosidase A in Fabry disease",

abstract = "Fabry disease is an inherited lysosomal storage disorder that is characterized by a deficiency in lysosomal α-D-galactosidase activity. One current therapeutic strategy involves enzyme replacement therapy, in which patients are treated with recombinant enzyme. Co-treatment with enzyme active-site stabilizers is advocated to increase treatment efficacy; a strategy that requires effective and selective enzyme stabilizers. Here, we describe the design and development of an α-D-gal-cyclophellitol cyclosulfamidate as a new class of neutral, conformationally-constrained competitive glycosidase inhibitor that acts by mimicry of the Michaelis complex conformation. We found that D-galactose-configured α-cyclosulfamidate 4 effectively stabilizes recombinant human α-D-galactosidase (agalsidase beta, Fabrazyme{\textregistered}) both in vitro and in cellulo.",

author = "Marta Artola and Christinne Hedberg and Rowland, {Rhianna J.} and Llu{\'i}s Raich and Kassiani Kytidou and Liang Wu and Amanda Schaafa and Ferraz, {Maria Joao} and {van der Marel}, {Gijsbert A.} and Cod{\'e}e, {Jeroen D. C.} and Carme Rovira and Aerts, {Johannes M. F. G.} and Davies, {Gideon J.} and Overkleeft, {Herman S.}",

note = "{\textcopyright} 2019",

year = "2019",

month = aug,

day = "20",

doi = "10.1039/C9SC03342D",

language = "English",

journal = "Chemical Science",

issn = "2041-6520",

publisher = "The Royal Society of Chemistry",

}

Artola, M, Hedberg, C, Rowland, RJ, Raich, L, Kytidou, K, Wu, L, Schaafa, A, Ferraz, MJ, van der Marel, GA, Codée, JDC, Rovira, C, Aerts, JMFG, Davies, GJ & Overkleeft, HS 2019, 'α-D-Gal-cyclophellitol cyclosulfamidate is a Michaelis complex analog that stabilizes therapeutic lysosomal α-galactosidase A in Fabry disease', Chemical Science. https://doi.org/10.1039/C9SC03342D

TY - JOUR

T1 - α-D-Gal-cyclophellitol cyclosulfamidate is a Michaelis complex analog that stabilizes therapeutic lysosomal α-galactosidase A in Fabry disease

AU - Artola, Marta

AU - Hedberg, Christinne

AU - Rowland, Rhianna J.

AU - Raich, Lluís

AU - Kytidou, Kassiani

AU - Wu, Liang

AU - Schaafa, Amanda

AU - Ferraz, Maria Joao

AU - van der Marel, Gijsbert A.

AU - Codée, Jeroen D. C.

AU - Rovira, Carme

AU - Aerts, Johannes M. F. G.

AU - Davies, Gideon J.

AU - Overkleeft, Herman S.

PY - 2019/8/20

Y1 - 2019/8/20

N2 - Fabry disease is an inherited lysosomal storage disorder that is characterized by a deficiency in lysosomal α-D-galactosidase activity. One current therapeutic strategy involves enzyme replacement therapy, in which patients are treated with recombinant enzyme. Co-treatment with enzyme active-site stabilizers is advocated to increase treatment efficacy; a strategy that requires effective and selective enzyme stabilizers. Here, we describe the design and development of an α-D-gal-cyclophellitol cyclosulfamidate as a new class of neutral, conformationally-constrained competitive glycosidase inhibitor that acts by mimicry of the Michaelis complex conformation. We found that D-galactose-configured α-cyclosulfamidate 4 effectively stabilizes recombinant human α-D-galactosidase (agalsidase beta, Fabrazyme®) both in vitro and in cellulo.

AB - Fabry disease is an inherited lysosomal storage disorder that is characterized by a deficiency in lysosomal α-D-galactosidase activity. One current therapeutic strategy involves enzyme replacement therapy, in which patients are treated with recombinant enzyme. Co-treatment with enzyme active-site stabilizers is advocated to increase treatment efficacy; a strategy that requires effective and selective enzyme stabilizers. Here, we describe the design and development of an α-D-gal-cyclophellitol cyclosulfamidate as a new class of neutral, conformationally-constrained competitive glycosidase inhibitor that acts by mimicry of the Michaelis complex conformation. We found that D-galactose-configured α-cyclosulfamidate 4 effectively stabilizes recombinant human α-D-galactosidase (agalsidase beta, Fabrazyme®) both in vitro and in cellulo.

U2 - 10.1039/C9SC03342D

DO - 10.1039/C9SC03342D

M3 - Article

SN - 2041-6520

JO - Chemical Science

JF - Chemical Science

ER -